Atomistic Studies of Nucleation and Oligomerization in Polyglutamine Aggregation

描述（由申请人提供）：我们的目标是获得对聚谷氨酰胺聚集成核和寡聚化机制的准确理解。我们的研究将基于分子模拟和荧光相关光谱（PCS）实验的结合。聚谷氨酰胺聚集是一种依赖于成核的过程，与包括亨廷顿氏病在内的九种不同神经系统疾病的发生和进展直接相关。鉴于毒性，鉴于早期中间体在形成大聚集体的途径上或关闭的毒性作用，成核机制的细节与体内聚集有关。为了判断聚谷氨酰胺聚集成核的不同建议，我们需要详细模拟含有聚谷氨酰胺的系统中的链寡聚化。为此，我们开发了一个高效准确的模拟引擎，使我们能够模拟不同长度的多个聚谷氨酰胺分子的构象和相平衡。这个名为ABSINTH的引擎是基于一种新的方法来模拟多肽与水的平均场相互作用以及多肽内部和多肽之间水介导的相互作用。我们现在可以通过寻找以下问题的答案来测试聚谷氨酰胺分子成核和寡聚化的特定假设：增加聚谷氨酰胺长度是否稳定分子内3-sheet或降低这些结构形成的屏障？2. 对于聚谷氨酰胺寡聚成核来说，不稳定的、部分膨胀的构象是否比亚稳的、紧凑的、3层的构象更适合于临界数量的3层接触？3. 整体溶剂质量和序列环境的扰动如何影响聚谷氨酰胺的构象波动以及这些波动如何改变聚谷氨酰胺的相行为？

DESCRIPTION (provided by applicant): Our goal is to obtain an accurate understanding of the mechanism of nucleation and oligomerization in polyglutamine aggregation. Our studies will be based on a combination of molecular simulations and fluorescence correlation spectroscopy (PCS) experiments. Polyglutamine aggregation, a nucleation- dependent process, is of direct relevance to the onset and progression of nine different neurological diseases, including Huntington's disease. Details of nucleation mechanisms are relevant for in vivo aggregation given the toxic given the toxic roles ascribed to early intermediates populated on or off the pathways to formation of large aggregates. To adjudicate between the different proposals for nucleation of polyglutamine aggregation, we need detailed simulations of chain oligomerization in systems containing polyglutamine. Toward this end, we developed an efficient and accurate simulation engine, which allows us to simulate conformational and phase equilibria for multiple polyglutamine molecules of varying lengths. This engine named ABSINTH, for Aggregation of Biomolecules Studied using Implicit Novel Tunable Hamiltonians is based on a new method for modeling mean-field interactions of polypeptides with water and water-mediated interactions within and between polypeptides. We can now test specific hypotheses for nucleation and oligomerization of polyglutamine molecules by seeking answers to questions listed below: 1. Does increasing polyglutamine length stabilize intramolecular 3-sheets or reduce the barrier to the formation of these structures? 2. Are unstable, partially swollen conformations characterized by a critical number of (3-sheet contacts better suited than metastable, compact, (3-sheets for nucleation of polyglutamine oligomerization? 3. How do perturbations in overall solvent quality and sequence context influence conformational fluctuations of polyglutamine and how do these fluctuations alter the phase behavior of polyglutamine?